Stroke and suicide among people with severe mental illnesses

The associations between people with severe mental illnesses (SMI) and the risks of stroke, suicide, and death remain unclear. We examined healthcare service usage among adults with and without SMI and explored the risk of stroke, suicide, and death. We divided 18–80-year-old adults with SMI into catastrophic and non-catastrophic illness groups. These groups were subjected to a 1:5:5 propensity score matching with people without SMI. Data on demographic characteristics, economic factors, environmental factors, comorbid conditions, self-injury behavior, the number of outpatients and ED visits, and hospitalization were collected. The primary outcomes were risks of stroke, suicide, and death. We included 19,570 people with catastrophic SMI, 97,850 with non-catastrophic SMI, and 97,850 controls. Patients with SMI, especially those with catastrophic illnesses, had higher stroke risk, suicide, and death than those without SMI. People with SMI used health services more frequently than those without SMI. Patients with a history of hospitalization or ED access had a higher risk of stroke, suicide, and death. Our data indicate that special attention should be given to patients with SMI, particularly those with a history of healthcare service utilization, such as through more extended hospital stays with high-intensity interventions.


Results
After 1:5:5 matching, 215,270 patients were included: 19,570 in the catastrophic SMI group, 97,850 in the SMI group, and 97,850 in the control group.Their characteristics are presented in Table 1.The mean age of the three groups was approximately 41 years.The distributions of sex, age groups, and CCI were not statistically different among the three groups after matching.In addition, the SMI groups had lower education levels, a lower proportion of married individuals, and lower incomes.Moreover, compared with the control group, the SMI groups had a higher percentage of patients with self-harm behavior, use of outpatient department (OPD) medical services, emergency services, and hospital admissions.
Table 2 presents the differences among the three groups by bivariate analysis of the log-rank test.Table 3 shows the results of the Cox proportional hazards model.After adjustment for the other variables, the highest risk of stroke was noted in the SMI group (HR = 1.33, 95% CI 1.22-1.45,p < 0.001), followed by the catastrophic SMI group (HR = 1.20, 95% CI 1.06-1.36,p = 0.004).The catastrophic SMI group had the highest risk of suicide (HR = 20.53,95% CI 15.50-27.19,p < 0.001) and death (HR = 2.60, 95% CI 2.41-2.80,p < 0.001; Table 3) comparing with those without SMI.
A history of self-harm was associated with a higher risk of suicide (HR = 3.12, 95% CI 1.72-5.67,p < 0.001).A higher frequency of outpatient visits was associated with a lower risk of death.ED visits and admission also were associated with the risk of stroke, suicide, and death (Table 3).According to the univariate Poisson regression test, the catastrophic SMI group had the highest incidence of stroke, suicide, and death (3.13, 3.05, and 11.94 per 1000 person-years, respectively), followed by the SMI group (2.79, 1.41, and 6.68 per 1000 person-years, respectively; Table 4).
Supplementary Figures A, B, and C present the covariate-adjusted cumulative incidence curves of stroke, suicide, and death among people with SMI compared with the control group according to the Cox proportional hazard model.

Discussion
In the current nationwide cohort study, we observed higher rates of stroke, suicide, and death in patients with SMI than in those without SMI.Patients with SMI with catastrophic illness certificates were at the highest risk.Additionally, people with SMI used health services more frequently than those without SMI.Patients hospitalized or accessed ED services were at higher risk of stroke, suicide, and death.However, patients with higher outpatient use had a lower risk of death, with no effect on stroke and suicide.Our results are similar to another population-based cohort study from New Zealand, which reported an association between psychiatric disorders and self-harm behavior 14 .Mental disorders were associated with the onset of physical illness, multiple physical illness diagnoses, higher hospitalizations, and early mortality 14 .
Our data indicated that SMI was associated with a higher risk of stroke, consistent with several studies 15,16 .A meta-analysis of six cohort studies confirmed a modest but significant positive association between schizophrenia and stroke morbidity and mortality 17 ; patients with BD had a significantly increased risk of stroke 18 .Numerous mechanisms have been proposed to explain the association between SMI and stroke.For instance, SMI correlates with adverse effects of drug therapy 19 and behavioral alterations such as smoking 20 , inadequate physical activity, and insufficient dietary/caloric intake 21 .These behavioral changes, in turn, are linked to the etiology of diverse diseases, including diabetes and cardiovascular disease, which could serve as contributors to the occurrence of stroke and premature mortality.In addition, insufficient health care availability 22 may increase natural-cause mortality in psychiatric patients.Disparities in mortality rates and reduced life expectancy serve as markers of health inequalities, and people with mental illness do not benefit equally from social and healthcare advancements experienced by the general population 23 .Because of the NHI program in Taiwan, in our study, patients with SMI had higher rates of medical service use than the controls, indicating no barriers to using medical services.Nonetheless, our data lacks specific information on medical care details and quality.This is our limitation in displaying the purpose of the medical service visit and the service quality.Besides, people with SMI are less likely to receive preventive care services (such as screening for cardiovascular risk factors) and high-quality care than those without SMI 24 .Moreover, certain research findings suggest challenges for individuals with SMI in effectively managing their chronic conditions 25 .Schizophrenia is correlated with a diminished likelihood of receiving high-quality diabetes care, contributing to an elevated risk of diabetes-related emergency department visits and hospitalizations 26 .Notably, there is a notable deficiency in the prescription of various common medications, particularly those addressing cardiovascular issues, in individuals with SMI, including those diagnosed www.nature.com/scientificreports/with schizophrenia 27 .Thus, considerable gaps remain in routine health care for many people with mental illness 24 .
These gaps include physicians focusing on mental illness rather than physical health, inconsistent adherence to health checks and treatment, and poor communication.Patients with SMI tend to have lower socioeconomic backgrounds, which may make it more difficult for them to use medical resources appropriately 23 .Taiwan's psychiatric medical care is highly developed and covered under the NHI, enabling people to seek treatment in community psychiatric clinics or hospitals; they can also go to other departments to receive medical treatment for physical diseases.In our study, we found that a relatively high proportion of older patients were first diagnosed with SMI between 2008 and 2011, considering the age at which SMI is most likely to occur.Our research relies on observations sourced from the National Health Insurance database, and the observed phenomenon might be attributed to the substantial time lapse between the onset and formal diagnosis of SMI.Diagnostic delays can stem from various factors, including patients' limited insight or societal taboos discouraging them from seeking medical treatment.Additionally, some instances arise from healthcare professionals downplaying the diagnosis of SMI and instead categorizing milder mental conditions as the primary diagnosis 28 .
We observed no increased suicide risk in new-onset strokes in patients with SMI.Selective survival and competing causes of death may explain this pattern.Individuals with lower socioeconomic status may die earlier for other reasons so that only the healthiest survive into old age 29 .It has been suggested that higher rates of selective survival among vulnerable, high-mortality populations lead to higher proportions of healthy older individuals who may have lower suicide rates.Because stroke is more common in old age 30 , those with SMI surviving into old age who develop stroke may not be at increased suicide risk.
In addition to a high risk of death from natural causes, SMI has also been associated with a higher risk of suicide 6,31 , consistent with our results.Furthermore, some studies have concluded that older adults have the highest suicide rates 32 , which also agrees with our data.In our analysis, a CCI score of ≥ 3 was associated with the highest suicide risk, in line with other studies 33 .Furthermore, consistent with Gallego et al. 34 , we observed that a history of suicide attempts was associated with higher suicide rates.This finding has been corroborated by large systematic reviews by Beghi et al. 35 , 76 studies, and Larkin et al. 36 , 129 studies.Therefore, patients aged ≥ 65 with SMIs, new arrivals to local mental health services, patients with multiple chronic diseases, divorced or widowed individuals, and those with low education levels should receive multidimensional assistance.
Studies have attempted to predict suicidal behavior from electronic health records.The factors predicting suicide include post-psychiatric hospitalization 37 , prediction of suicide or accidental death following civilian general hospital discharge 38 , and prediction of suicide attempt or suicide following outpatient visits.For example, Barak-Corren and colleagues 39 used health records data from two large academic health systems to predict suicide attempts or deaths among outpatients with ≥ 3 visits.In our analysis, we observed that suicide cases had a higher rate of ED visits, hospitalization, and previous self-harm records.These characteristics may be helpful for the prediction of suicide in the Taiwanese medical service system.
Given this clinically significant overlap, patients with mental illness should be asked if they have used medical services adequately.It remains unclear what proportion of physical health needs and treatment is unmet in this population compared with individuals without documented mental illness.However, epidemiologic research in community and clinical settings reveals a strong association between mental disorders and increased healthcare service utilization 40 .Psychiatric disorders are often associated with frequent outpatient services in Taiwan 41 .Analytical results do not replace clinical judgment, but risk scores can inform individual clinical decision-making and quality improvement plans.Our results may help provide a risk score to help determine risk stratification.We will also suggest further studies related to "mortality risk factors associated with severe mental illnesses" and "reasons associated with emergency department visits and hospitalizations for SMI patients."

Strengths and limitations
This study used a national population database to avoid selection and participation bias 42 .Other strengths include the large sample size and number of events and the long follow-up time, which increase the likelihood of finding significance even if the differences are slight; therefore, all results should be interpreted in terms of the clinical importance of the differences and provide strong evidence for understanding possible factors in the real world.This study has several limitations.First, the NHIRD lacks data on important confounders for increased stroke and mortality, including smoking, dietary habits, and physical activity, precluding the adjustment for these confounders in our regression models.Second, health system records do not reflect crucial social risk factors for suicidal behavior, such as unemployment, bereavement, or relationship breakdown.Suicidal behavior may reflect an interaction of clinical risk factors, adverse life events, and available means of self-harm.Moreover, the monthly income is based on NHI premium-based salary and not actual income data.Third, no information is available on the severity of illness at the time of suicide.The lack of seriousness and clinical status of SMI precludes the determination of the association between mental status and outcome.However, we tried to use the catastrophic disease system to help define severity.Our results are still valid as a reference for clinical care.Fourth, we lack information on substance abuse.The prevalence of comorbidity between SMI and substance use disorder (SUD) is substantial, with estimates indicating that up to 75% of SMI patients also have SUD, and approximately 60% of adults with SUD exhibit some form of SMI.The presence of coexisting disorders is associated with an increased likelihood of adverse health outcomes, suicide, unplanned hospital admissions, and premature mortality 43 .

Clinical implications
The higher rates of stroke, suicide, and death in our cohort of patients with SMI suggest that special attention should be given to their health and well-being and strategies to improve them.Our data indicate that the higher the ED utilization and hospitalization rate, the higher the risk of suicide, stroke, and death.These findings highlight opportunities to improve both disease and suicide prevention.A significant effort to prevent suicide in all patients with SMI in the ED appears warranted, especially among those with self-harming behaviors, multiple chronic diseases, and high ED utilization.Hospitalization is also a risk of death by suicide compared with people who are not hospitalized.The period of hospitalization provides an opportunity for potentially high-intensity interventions.When dealing with patients with SMI, clinicians should consider more extended hospital stays, which may help initiate high-intensity physical and mental health interventions, before discharging them to outpatient care.Additionally, it is crucial for clinicians to prioritize individuals with high ED and hospitalization utilization, as they may harbor potential SMI cases.Developing a model for case management could aid in enhancing the health condition of these patients and potentially reduce the overutilization of medical services.

Data sources
This nationwide population-based cohort study used data from Taiwan's National Health Insurance Research Database (NHIRD) 44 .In addition, in this study, we used the Longitudinal Health Insurance Database, the Taiwan Cause of Death Statistics, and the Household Registration File managed by the Ministry of the Interior.These databases were provided by the Health and Welfare Data Science Center under the Ministry of Health and Welfare (MOHW).Personally identifiable information was de-identified before its release.Therefore, the collected data comply with personal data protection regulations.

Study population
The data of patients aged 18-80 who received the first diagnosis of SMI between 2008 and 2010 were extracted from the NHIRD.SMI was identified through International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes as follows: at least one instance of hospitalization or ≥ three outpatient visits within 365 days with the diagnosis of depression (ICD-9-CM: 296.2X, 296.3X, 300.4X),BD (ICD-9-CM: 296.XX, excluding 296.2X and 296.3X), or schizophrenia (ICD-9-CM: 295.XX), respectively.This study divided patients with SMI into catastrophic and non-catastrophic illness groups.The index date for these two groups was the date of the new diagnosis, and that for the control group was the first day of the matching year.The catastrophic illness group comprised patients a physician diagnosed as having a "catastrophic illness" and a catastrophic illness certificate dated between 2008 and 2010.People with serious illnesses who met the National Health Insurance's definition of catastrophic illnesses as diagnosed by physicians, including 30 categories of patients such as cancers, chronic mental illness, chronic renal failure, type I diabetes, autoimmune disease, congenital factor disorder, stroke, congenital hypothyroidism, etc. Patients with catastrophic illnesses were exempted from copayment and thus avoided financial burden for its long-term health care.Psychiatric conditions such as schizophrenia, schizoaffective disorder, BD, and major depressive disorder may be considered.In cases where a patient exhibits a decline in occupational function, the physician assists them in obtaining a certificate for catastrophic illnesses.Patients with a catastrophic illness certificate receive care for a disease or related condition within the certificate's validity period, without paying out-of-pocket costs for outpatient or inpatient treatment.However, these patients must follow standard treatment and payment procedures when seeking care for unrelated illnesses 45 .
For the control group, 3 million cases were randomly selected from the National Health Insurance Beneficiaries File, and those with a primary or secondary diagnosis of SMI from 2000 to 2017 were excluded.To reduce substantial differences in patient characteristics between the three groups, a 1:5:5 propensity score matching was conducted among the catastrophic illness, illness, and control groups year by year according to sex, age, and severity of comorbidities, thereby decreasing the selection bias.A greedy nearest neighbor algorithm was used for matching.In addition, we excluded individuals with a diagnosis of any catastrophic illness other than depression, BD, and schizophrenia, as well as those diagnosed as having cancer or stroke before the index year.The patient selection flowchart is presented in Fig. 1.

Definition of variables
In this study, the following variables were included:

Table 1 .
Baseline characteristics of people with severe mental illness (SMI) with catastrophic illness certificate, matched people with SMI but no catastrophic illness certificate and matched people without SMI.& χ 2 test; Index date: the date with newly diagnosed depression, bipolar disorder, or schizophrenia for the first time from 2008 to 2010.

Table 2 .
The distribution of stroke, suicide, and death among patients with severe mental illness (SMI) with catastrophic illness certificate, matched people with SMI but no catastrophic illness certificate, and matched people without SMI.& Log-rank test.

Table 3 .
Risk factors of stroke, suicide, and death among patients with severe mental illness (SMI) with catastrophic illness certificate, matched people with SMI but no catastrophic illness certificate, and matched people without SMI by Cox Proportional Hazard Model.& Conditional Cox proportional hazard model.

Table 4 .
Incidence per thousand person-years of stroke, suicide, and death among patients with severe mental illness (SMI) with catastrophic illness certificate, matched patients with SMI but no catastrophic illness certificate, and matched people without SMI.& Univariate Poisson regression test for Poisson distribution.